Methods for treating cancerous tumors

ABSTRACT

Apparatuses and methods described herein relate to treating cancerous tumors using radiation therapy and chemotherapy. In some embodiments, a method of treatment includes administering radiation therapy targeting a tumor, isolating a segment of a vessel proximate to the tumor, and administering a dose of a chemotherapeutic agent to the segment of the vessel. The method can further include waiting a period of time after administering the radiation therapy before administering the dose of the chemotherapeutic agent. In some embodiments, a catheter device including first and second occluding elements can be used to isolate the segment of the vessel.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalPatent Application No. 62/507,962, titled “Methods for TreatingCancerous Tumors,” filed May 18, 2017, the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND

Cancer begins when a cell begins dividing uncontrollably. Eventually,these cells form a visible mass or tumor. Solid tumors are masses ofabnormal tissue that originate in organs or soft tissues that typicallydo not include fluid areas. Some examples of solid tumors include:pancreatic cancer, lung cancer, brain cancer, liver cancer, uterinecancer, and colon cancer.

Traditionally, tumors have been treated with surgical resection,radiation, and/or chemotherapy. Surgical resection involves the removalof tumor tissue. Radiation uses beams of intense energy to kill cancercells and to shrink tumors. And chemotherapy involves the use oftherapeutic agents or drugs to treat cancer. But surgical resection maynot completely remove a tumor. Radiation and chemotherapy can haveundesirable systemic side effects, including extreme fatigue, hair loss,infection, nausea and vomiting, and others that limit their usefulness.More recently, direct activation of the patient's immune system toattack cancerous cells has shown promise in treating certain solidtumors, but not all. Thus, the need for an improvement in both thesafety and the efficacy of current therapy still exists.

Use of localized intra-arterial therapies, including trans-arterialchemo-delivery (TAC) or trans-arterial chemo-embolization (TACE), hasbeen shown to be clinically beneficial for a certain subset of solidtumors. TAC or TACE can involve imaging an organ having a tumor usingangiography, isolating a branch of the artery that feeds the tumor orportion of the organ containing the tumor, and then locally injectingchemotherapy in a bolus fashion via the isolated artery. Localizedintra-arterial therapies allow higher drug concentration to reach thetumor, overcoming the problem of poor blood flow to tumor mass incomparison to healthy tissue. Furthermore, localized intra-arterialtherapies can also take advantage of the first pass effect ofchemotherapeutics by generating higher level drug concentrations at thetumor cell membrane and therefore enhancing cellular drug uptake ascompared to non-localized infusion. Lastly, local delivery can reducesystemic side effects of chemotherapy.

One of the limitations of TAC and TACE is the need for selectivecannulation and isolation of the tumor feeder vessel or arterial branchthat can target the smallest portion of the organ containing the tumor.But it may be difficult to target and limit drug delivery to a smallportion of the organ containing the tumor while achieving desiredefficacy levels with the cancer treatment. On the one hand, limitingdrug delivery to a small portion of the organ can reduce the potentialimpact of the administered drug on surrounding healthy tissue. But onthe other hand, when the isolated region becomes too small, drug uptakelevels by the tumor may decrease and reduce the efficacy of the cancertreatment. Given these limitations, a method to deliver a sufficientdose of a chemotherapeutic drug in addition to and independent of theneed to cannulate and isolate to a specific feeding/supplying branch ofa tumor feeder vessel is highly desirable.

Pancreatic Cancer

In 2016, pancreatic cancer ranked as the fourth leading cause of cancerdeath in the United States, and the tenth most commonly diagnosed tumortype in men and women. Estimates of incidence and deaths caused bypancreatic cancer are approximately 53,070 and 41,780, respectively(American Cancer Society: Cancer Facts and Figures, American CancerSociety, 2016). Projections based on the changing demographics of theUnited States population and changes in incidence and death rates revealthat, unless earlier diagnosis is made possible or better treatmentoptions become available, pancreatic cancer is anticipated to move fromthe fourth to the second leading cause of cancer death in the UnitedStates by 2020.

Systemic chemotherapy as treatment for pancreatic cancer may be modestlyeffective due to low drug penetration in the pancreas because a druginfused systemically only moderately penetrates the pancreas, which maygenerally increase toxicity within a patient's body but not have aneffect on the cancer. In many instances, tumors located in the pancreasare located in tissue surrounding an artery but not in a region of anartery that can be targeted and isolated. Accordingly, it may bedifficult for a biologic agent or drug to reach and treat the tumors.Among solid tumors, drug delivery to pancreatic tumors is especiallydifficult due to the hypo-vascular and poorly perfused nature of thepancreas. The unique environment of the pancreas lends itself to reduceddrug levels within the organ tissue, which reduces the effectiveness ofsystemic chemotherapy that relies on a functional vasculature fordelivery to tumor cells. Also, the effect of chemotherapy isconcentration dependent, and systemic infusion oftentimes results in lowconcentrations. Aside from dosing limitations in treating pancreaticcancer, many systemic side effects of chemotherapeutic agents can resultfrom the treatment.

In an attempt to increase the effectiveness of chemotherapeutic agentson pancreatic tumors while decreasing systemic toxicity, variousresearchers have delivered drugs directly to the pancreas usingtraditional endovascular catheters. These initial attempts have beenlimited due to the redundant nature of blood supply to the pancreas andits adjacent organs. Non-selective engagement of the pancreatic vesselscan also lead to the wash through of chemotherapy to other adjacentorgans. Most of the arterial branches to the pancreas are small; thus,selective engagement of these small branches via conventional cathetersis difficult. Thus, there is a need to address these and otherdeficiencies.

Lung Cancer

Lung cancer is another deadly cancer that is difficult to treat. Lungcancer is responsible for 23% of total cancer deaths. Long-term exposureto tobacco smoke causes 80 to 90% of lung cancers. Nonsmokers accountfor 10 to 15% of lung cancer cases, and these cases are often attributedto a combination of genetic factors or other environmental exposures(Vogl, T. J., et al., Seminars in Interventional Radiology, 2013, 30(2):176-184).

Common treatments for lung cancer depend on the cancer's specificpathology, staging, and the patient's performance status (e.g., abilityto breath). Traditional treatment options are surgery, chemotherapy,immunotherapy, radiation therapy, and palliative care. Intravasculartechniques for localized delivery of chemotherapeutic agents have alsobeen used to treat lung cancer, and include cancer therapy such asarterial chemoembolization, bronchial artery infusion (BAI), isolatedlung perfusion (ILP), and lung suffusion. Chemotherapeutics approved forthe treatment of non-small cell lung cancer in the United States includemethotrexate, paclitaxel albumin-stabilized nanoparticle formulation,afatinib dimaleate, everolimus, alectinib, pemetrexed di sodium,atezolizumab, bevacizumab, carboplatin, ceritinib, crizotinib,ramucirumab, docetaxel, erlotinib hydrochloride, gefitinib, afatinibdimaleate, gemcitabine hydrochloride, pembrolizumab, mechlorethaminehydrochloride, methotrexate, vinorelbine tartrate, necitumumab,nivolumab, paclitaxel, ramucirumab, and osimertinib, and thecombinations carboplatin-taxol and gemcitabine-ci splatin(https://www.cancer.gov/aboutcancer). Drugs approved for the treatmentof small cell lung cancer include methotrexate, everolimus, doxorubicinhydrochloride, etoposide phosphate, topotecan hydrochloride,mechlorethamine hydrochloride, and topotecan(https://www.cancer.gov/aboutcancer). Lung cancer such as small celllung cancer can sometimes be treated with a combination of radiationtherapy and one or more chemotherapeutics. But other types of lungcancer such as non-small cell lung cancer may not be sensitive tocurrent chemotherapeutics. In many instances, current treatment methodsare not effective at providing meaningful treatment or palliative care.Thus, it is desirable to have a more effective method for treating lungcancer tumors.

Brain Cancer

Malignant gliomas comprise up to 80% of primary malignant brain tumorsin the adults. Among these, glioblastomas are the most deadly andaccount for 82% of all malignant gliomas (Suryadevra, C. M., et al.,Surg. Neurol. Int., 2015, 6(1):S68-S77). The current standard of careincludes surgical resection, followed by adjuvant external beamradiation and chemotherapy with drugs such as temozolomide. Conventionaltherapy is nonspecific and often results in a tragic destruction ofhealthy brain tissue. These treatments can be incapacitating and producea median overall survival of just twelve to fifteen months. In addition,the invasive properties of glioblastomas make complete resectiondifficult and the glioblastomas may recur following initial treatment.Malignant gliomas are also highly vascularized tumors, and their uniquecapacities for regulating angiogenesis contribute to their resistanceagainst known therapies.

Malignant gliomas, including glioblastoma multiforme, have been treatedwith inter-arterial chemotherapy. Typically, a catheter is inserted inthe femoral artery and ends in the carotid artery, while a separatemicrocatheter is also inserted into the femoral artery and used toexplore the specific vessels feeding the tumor for administration of thechemotherapy (Burkhardt, J-K., et al., Interventional Radiology, 2011,17:286-295). But such methods are not always effective and can beimproved.

Liver Cancer

Liver cancer is another difficult-to-treat cancer characterized by solidtumors. In 2016, an estimated 39,230 adults (28,410 men and 10,820women) in the United States will be diagnosed with primary liver cancer.Liver cancer also commonly metastasizes to other parts of the body. Itis estimated that 27,170 deaths (18,280 men and 8,890 women) from thisdisease will occur this year. Liver cancer is the tenth most commoncancer and the fifth most common cause of cancer death among men. It isalso the eighth most common cause of cancer death among women (AmericanCancer Society: Cancer Facts and Figures, American Cancer Society,2016). When compared with the United States, liver cancer is much morecommon in developing countries within Africa and East Asia. In somecountries, it is the most common cancer type. The one-year survival ratefor people with liver cancer is 44%. The five-year survival rate is 17%.For the 43% of people who are diagnosed at an early stage, the five-yearsurvival rate is 31%, while it is only 11% if the cancer has spread tosurrounding tissues or organs and/or the regional lymph nodes. If thecancer has spread to a distant part of the body, the 5-year survivalrate is only 3%(http://www.cancer.net/cancer-types/liver-cancer/statistics).

Currently, patients with hepatocellular carcinoma and cirrhosis arefrequently treated with non-specific trans-arterial therapy usingtechniques that deliver treatments directly into the liver (Lewandowski,R. J., et al., Radiology, 2011, 259(3):641-657). Physicians use thefermoral artery to gain access to the hepatic artery, one of two bloodvessels that feed the liver. Trans-arterial therapy such as TACEinvolves delivery of chemotherapy directly to the liver, followed by aprocess to embolize the chemotherapy. In this therapy, a thick, oilysubstance (for example, Lipiodol) is mixed with chemotherapy (forexample, floxuridine, sorafenib tosylate or a mixture of platinol,mitomycin, and adriamycin) and injected under radiological guidancedirectly into the artery supplying the tumor via a catheter. TheLipiodol, or other particles, helps to contain the chemotherapy withinthe tumor and blocks further blood flow, thus cutting off the tumor'sfood and oxygen supply. TACE with doxorubicin-filled beads delivers thebeads directly to the liver, which releases chemotherapy slowly overtime and also blocks the blood flow to the tumor. In a similar therapy,radioactive yttrium beads are delivered via a catheter into the hepaticartery. The beads deliver radiation to the tumor, which kills the tumorcells, although other unintended areas of the liver may also receiveradiation, creating undesirable destruction of healthy tissue. Thus,there is a need to improve current treatment methods.

Uterine Cancer

In 2016, an estimated 60,050 women in the United States were diagnosedwith uterine endometrial cancer, with an estimated 10,470 deathsoccurring(http://www.cancer.net/cancer-types/uterine-cancer/statistics). Uterinecancer is the fourth most common cancer for women in the United States.The incidence of endometrial cancer is rising, mainly due to a rise inobesity, which is an important risk factor for this disease. It is thesixth most common cause of cancer death among women in the United Stateswith the 5-year survival rate being 82%.

Concurrent chemoradiotherapy (CCRT) is the main treatment for locallyadvanced cervical cancer. Neoadjuvant chemotherapy (NAC) was widelyemployed until CCRT became the standard, and conflicting results havebeen reported. Neoadjuvant intra-arterial chemotherapy (IANAC) isanother method for delivering NAC as an alternative to systemicchemotherapy. IANAC has been reported to achieve beneficial results thatcannot be obtained by systemic chemotherapy or CCRT. Kawaguchi et al.have reported that IANAC with cisplatin followed by radical hysterectomyor radiotherapy afforded similar results to concurrent chemoradiotherapyfor stage IIIB cervical cancer (Kawaguchi et al., World Journal ofOncology, 2013, 4(6):221-229). Drugs approved for use in the UnitedStates for the treatment of cervical cancer include bevacizumab,bleomycin, and topotecan hydrochloride, and the combinationgemcitabine-cisplatin. Uterine cancer of endometrial origin may betreated with, for example, megestrol acetate. But many systemic sideeffects of chemotherapeutic agents can result from current treatmentmethods. It is desirable to have a specific means of targeting uterinetumors.

Colon Cancer

In the United States, colorectal cancer is the fourth most common cancerdiagnosed each year for all adults combined. Separately, it is the thirdmost common cancer in men and third most common cancer in women. In2016, an estimated 134,490 adults in the United States were diagnosedwith colorectal cancer, with 95,270 new cases of colon cancer and 39,220new cases of rectal cancer. It is estimated that 49,190 deaths (26,020men and 23,170 women) were attributed to colon or rectal cancer in 2016.Colorectal cancer is the second leading cause of cancer death in theUnited States, although when it is detected early, it can often becured. The death rate from this type of cancer has been declining sincethe mid-1980s, probably because of an improvement in early diagnosis.The 5-year survival rate colorectal cancer is 65%, while the 10-yearsurvival rate is 58% (http://www.cancer.net/node/18707).

When possible, surgical removal of colorectal tumors is the treatment ofchoice as it can eliminate the cancer completely. However, metastasis toother organs, particularly the liver and the lung, is common andcomplicates the treatment of colon and rectal cancer dramatically. It istherefore desirable to have a method of treating metastasized colon andrectal cancers that are present in other organs of the body. Drugsapproved for use in treating colon cancer in the United States includebevacizumab, irinotecan hydrochloride, capecitabine, cetuximab,ramucirumab, oxaliplatin, 5-FU, fluorouracil, leucovorin calcium,trifluridine, tipiracil hydrochloride, oxaliplatin, panitumumab,ramucirumab, regorafenib, ziv-aflibercept and the combinations capox,folfiri-bevacizumab, folfiri-cetuximab, FU-LV, xeliri and xelox.

SUMMARY OF THE INVENTION

Apparatuses and methods are described herein that relate to, forexample, the treatment of cancerous tumors. In some embodiments, themethod comprises: a) first administering a course of radiation therapytargeting an area including a solid tumor; b) second waiting a period oftime for the radiation to take effect on the vasculature in the area;and c) third administering a therapeutically effective dose of achemotherapeutic agent to an isolated arterial section near the solidtumor.

In some embodiments, the method comprises: a) first administering atargeted dose of radiation to an area including a solid tumor; b) secondwaiting a period of time; c) third isolating an area containing acancerous tumor by, for example, isolating an arterial segment proximateto the tumor; and d) fourth administering a localized therapeuticallyeffective dose of a chemotherapeutic agent.

In some embodiments, the method comprises: a) administering a course ofradiation therapy to an area including a solid tumor; b) isolating theproximal and the distal part of the vasculature closest to the tumor toproduce an isolated arterial segment; c) decreasing the intraluminalpressure of the isolated arterial segment to the level of theinterstitium; and d) administering a therapeutically effective dose of achemotherapeutic drug. In one embodiment, the method comprises anadditional step of waiting a period of time following the step ofadministering the course of radiation therapy.

In some embodiments, the method includes delivering radiation therapy toa target area including a tumor; and inserting a catheter device into anartery where the catheter device includes a first occlusion member, asecond occlusion member, and a body defining a lumen in fluidcommunication with an infusion port. The infusion port is disposedbetween the first occlusion member and the second occlusion member. Thefirst occlusion member and the second occlusion member are moved to anarea of the artery disposed proximate to the target area. The firstocclusion member and the second occlusion member are deployed to isolatethe area of the artery disposed proximate to the target area. A dose ofchemotherapeutic agent is then delivered to the isolated area of theartery via the lumen and the infusion port. The chemotherapeutic agentpermeates to the target area including the tumor from the isolated areaof the artery.

In some embodiments, the method includes administering a dose ofradiation to a target area including a tumor; inserting a catheterdevice into a vessel, the catheter device including a first occlusionelement and a second occlusion element; isolating a segment of thevessel proximate to the target area using the first occlusion elementand the second occlusion element; and delivering a dose of an agent tothe segment via the catheter device.

In some embodiments, the method includes administering a dose ofradiation to a target area including a tumor; isolating a segment of thevessel proximate to the target area; adjusting an intraluminal pressureof the segment to a level of pressure of an interstitial space betweenthe vessel and the target area; and delivering a dose of an agent to thesegment via the catheter device.

Other objects of the invention may be apparent to one skilled in the artupon reading the following specification and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 is an illustration of a catheter device disposed within a vessel,according to an embodiment.

FIG. 2 is a flowchart illustrating a method for treating a canceroustumor, according to embodiments described herein.

FIG. 3 is a graph showing a change in pressure (mmHg) in a vessel overtime while undergoing treatment, according to an embodiment.

FIG. 4A is schematic illustration of a catheter device shown in adilated configuration disposed within a vessel, according to anembodiment.

FIG. 4B is a schematic illustration of dispersal of an infused agentinto tissue surrounding a vessel, according to an embodiment.

FIG. 5 is a flowchart illustrating a method for treating a canceroustumor, according to embodiments described herein.

FIG. 6A is an illustration of dispersal of an infused agent into tissuesurrounding a vessel without application of radiation therapy, and FIG.6B is an illustration of dispersal of an infused agent into tissuesurrounding a vessel with application of radiation therapy, according toembodiments described herein.

FIG. 7 is an image of a pancreatic tumor after undergoing treatmentaccording to methods described herein.

FIG. 8 is an image showing penetration of infused agents into tissuesurrounding a vessel via the microvasculature, according to anembodiment.

FIG. 9 is a graph comparing survival rates of patients treated accordingto different methods described herein.

FIG. 10 is a bar chart comparing survival rates of patients treatedaccording to different methods described herein.

FIG. 11 is an image of a catheter device disposed in a vessel in apatient's groin area, according to an embodiment.

FIG. 12 is an image showing penetration of an infused agent into tissuesurrounding a vessel after undergoing treatment, according to anembodiment.

DETAILED DESCRIPTION OF THE INVENTION

This application is not limited to particular methodologies or thespecific compositions described. It is also understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present application will be limited only by the appended claims andtheir equivalents.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present application, the preferredmethods and materials are now described.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the,” include plural referents unless the context clearlydictates otherwise. Thus, for example, the term “chemotherapeutic” isintended to mean a single chemotherapeutic or a combination ofchemotherapeutics; “a course of radiation therapy” is intended to meanone or more courses of radiation therapies, or combinations thereof; theterm “agent” is intended to mean a single agent or a combination ofagents, and so on and so forth.

As utilized in accordance with the present disclosure, the followingterms, unless otherwise indicated, shall be understood to have thefollowing meanings:

The words “proximal” and “distal” refer to direction closer to and awayfrom, respectively, an operator (e.g., surgeon, physician, nurse,technician, etc.) who would insert the medical device into the patient,with the tip-end (i.e., distal end) of the device inserted inside apatient's body first. Thus, for example, the implant end first insertedinside the patient's body would be the distal end of the implant, whilethe implant end to last enter the patient's body would be the proximalend of the implant.

“Treat”, “treating” and “treatment” of cancerous tumors refer toreducing the frequency of symptoms of cancer (including eliminating thementirely), avoiding the occurrence of cancer, and/or reducing theseverity of symptoms of cancer.

“Therapeutically effective amount” and “therapeutically effective dose”means the amount or dosage of a compound that, when administered to apatient for treating cancerous tumors, is sufficient to effect suchtreatment. The “therapeutically effective amount” or “therapeuticallyeffective dose” will vary depending on, for example, the compound, thesize of the tumor, and the age, weight, etc., of the patient to betreated.

OVERVIEW OF THE INVENTION

The present application provides a method for treating or amelioratingsolid cancerous tumors, wherein a course of targeted radiation therapyis first administered to an area including one or more tumors. A periodof time is allowed to elapse in order for the radiation to take effectin down-sizing the tumor(s). The radiation may also reduce themicrovasculature in the tissue in the area including the tumor(s). Thisperiod is followed by the administration of a therapeutically effectiveamount of a chemotherapeutic agent to an isolated arterial section nearthe solid tumor. Isolation of the arterial section may be accomplishedby isolating the proximal and the distal part of the vasculature closestto the tumor whereby the intraluminal pressure is then decreased to thelevel of the interstitium. The therapeutically effective dose of thechemotherapeutic agent may then be administered via infusion.Combination of radiation therapy followed by properly administeredchemotherapy is complementary and has a synergistic clinical effect whencombined.

Intra-arterial delivery of chemotherapy, including TAC and TACE, hasbeen shown to be effective and safe in treatment of certain solidtumors. A prerequisite for effective TAC or TACE is the selectiveengagement of nearby arterial vessels and, more commonly, the vesselsfeeding the tumor itself. The precise engagement of the feeding orbranch vessel remains a major limitation for expanding the use of TACEand TAC in solid tumors, including but not limited to, pancreaticadenocarcinoma. The isolation of the artery supplying the tumor or therelevant tissue can be a technical challenge for a number of reasons,for example: a) there are organs with no dedicated single blood vesselsupplying those specific organs; b) side and terminal branches of anartery can cause collateral flow to tissues and organs beyond the areaof interest; and c) the tumor feeder vessels may be too small fordetection by angiography; and d) the feeding branch/artery cannot becannulated.

To address these problems, methods disclosed herein may involveadministering radiation therapy to an area including a tumor. Theradiation may reduce the microvasculature in the tissue in the areaincluding the tumor. After the radiation therapy, the proximal and thedistal part of the vasculature (e.g., an artery) closest to the tumor isisolated using a double balloon catheter. Both the side and the terminalbranches are excluded, which prevents drug washout. The reducedmicrovasculature in the tissue in the area also reduces drug washout.Upon inflation of both balloons in the isolated arterial segment, theintra-luminal pressure is reduced to the level of interstitium(typically, 10-20 mmHg). A therapeutic agent such as, for example, achemotherapeutic drug, can be infused into the isolated arterialsegment. The infusion of the chemotherapeutic drug in the isolatedregion, without any major runoff, leads to an increase in theintra-luminal pressure of at least about 30 mmHg in the isolated vesselsegment. The pressure gradient forces the infused agent to traverse thearterial wall and enter the surrounding tissue, especially the vasavasorum surrounding the vessel wall, with subsequent influx of thetherapeutic agent into the tissue. This technique is referred to hereinas “trans-arterial micro-perfusion” or TAMP.

According to certain embodiments described herein, TAMP is not dependenton angiographic identification and cannulization of the tumor arterialsupply or feeding vessels and thus overcomes deficiencies of currenttechniques. In TAMP, the drug traverses the arterial wall (e.g.,endothelium and media) before entering into the adventitia andinterstitium. The interstitial concentration achieved is dependent onboth the influx of the drug into the tissue across the artery wall andthe efflux of the drug out of the interstitium via capillaries in thetissue area and the venous system. Hence, one can increase localizedtissue concentration by both increasing the influx and reducing theefflux using the approach described above. The infusion parameters thatdetermine the influx of the drug via TAMP include, but are not limitedto, the intraluminal pressure achieved between the balloons, theintraluminal drug concentration, and the duration of infusion. Byvarying these parameters, one can change the drug influx andinterstitial concentration.

In some embodiments, catheter devices such as those described in U.S.patent application Ser. No. 14/293,603, filed Jun. 2, 2014, titled“Devices, methods and kits for delivery of therapeutic materials to atarget artery,” now issued as U.S. Pat. No. 9,457,171, and U.S. patentapplication Ser. No. 14/958,428, filed Dec. 3, 2015, titled “Occlusioncatheter system and methods of use,” the disclosures of which areincorporated herein by reference, can be used and/or adapted for usewith TAMP techniques described herein. FIG. 1 depicts an examplecatheter device 100. The catheter device 100 includes a first occlusionelement 102 and a second occlusion element 104. The occlusion elements102, 104 can be any suitable devices or mechanisms that are configuredto selectively limit, block, obstruct, or otherwise occlude a bodilylumen (e.g., artery) in which the occlusion elements 102, 104 aredisposed. For example, in some embodiments, the occlusion elements 102,104 can be inflatable balloons or the like that can be transitionedbetween a collapsed (e.g., deflated) configuration and an expanded(e.g., inflated) configuration. The first occlusion element 102 can becoupled to a distal end portion of a first catheter, and the secondocclusion element 104 can be coupled to the distal end portion of asecond catheter. Alternatively, in some embodiments, the first occlusionelement 102 and the second occlusion element 104 can be coupled to asingle catheter at different points along the catheter. The catheterdevice 100 can be used to isolate a segment 120 of a bodily lumen (e.g.,artery) within the space defined between the first occlusion element 102and the second occlusion element 104. After the segment 120 is isolated,a procedure can be performed within the isolated segment 120 such as,for example, delivering a therapeutic agent to the isolated segment 120and surrounding tissue 110.

FIG. 2 illustrates a method 200 for performing a TAMP procedure. Themethod includes introducing a catheter (e.g., the catheter device 100)into a mammalian body into a bodily lumen (e.g., artery), at 202. Thecatheter can be advanced to a target area, at 204, and used to isolatethe target area, at 206. In some embodiments, the catheter can includetwo occlusion members (e.g., occlusion elements 102, 104) that can bedeployed (e.g., inflated) to isolate a segment of the bodily lumen toexclude the segment from its side and terminal branches. For example, afirst occlusion member (e.g., a distal occlusion element) can beinflated, at 207, and a second occlusion member can be inflated (e.g., aproximal occlusion element), at 208. After the occlusion elements aredeployed, an agent can be injected through an injection port of thecatheter device to the isolated segment disposed between the twoocclusion members, at 210. In some embodiments, a contrast dye can becan be injected into the isolated segment and the surrounding area canbe visualized to determine whether the segment has been correctlyisolated. For example, the injection of contrast through the infusionport can ensure that no extra vessels or bodily lumens are included inthe isolated area. If desired, the catheter can be moved and theprocedure repeated until the clinician can confirm that the catheter iscorrectly positioned. After the positioning of the catheter isconfirmed, a therapeutic cell/biologic/agent can be introduced to theisolated segment through the infusion port.

FIG. 3 graphically illustrates how pressure (mmHg) in a bodily lumen(e.g., artery) changes over time as a TAMP procedure is performed (e.g.,method 200). As shown in FIG. 3, the pressure in the bodily lumen dropswhen a first balloon or occlusion element is inflated and continues todrop until a second balloon or occlusion element is inflated. Thepressure then increases when an agent (e.g., a contrast dye, atherapeutic agent) is infused into the segment isolated by the firstballoon and the second balloon.

FIGS. 4A and 4B schematically depict an example of a catheter device 300disposed within a bodily lumen 310 (e.g., artery) and the dispersal ofan infused agent 360 through the bodily lumen 310 into surroundingtissue. According to methods described herein (e.g., method 200), theinfused agent 360 can be injected into an isolated segment 320 andallowed to infuse into the surrounding tissue via, for example, aconcentration gradient. As shown in FIG. 4B, the infused agent 360 caninfuse through a wall 312 of the bodily lumen 310 into the surroundingtissue. As shown, the concentration of the agent 360 decreases as thedistance (shown in millimeters (mm)) from the isolated segment 320 ofthe bodily lumen 310 increases.

In combination with the techniques described above, if one can decreasethe tissue efflux of the chemotherapeutic drug, the drug concentrationnear an isolated segment of a bodily lumen may be advantageouslyincreased. When a tumor is located in this region, the increasedconcentration can increase the effect of the chemotherapeutic drug onthe tumor. One technique that can decrease tissue efflux is to radiatethe tissue prior to treatment. Radiation can decrease tissuemicrovasculature in tissue containing cancerous tumors. Thus, combiningprior radiation to decrease tissue microvasculature with TAMP can have asynergistic effect. Combining the steps of radiation of the canceroustissue prior to the treatment, waiting two or more weeks for themicrovasculature to decrease, followed by use of the TAMP technique todeliver chemotherapy in the isolated segment of the bodily lumen (e.g.,artery) closest to the tumor, produces a synergistic effect that the useof the TAMP technique alone does not.

Methods described herein can be used to treat solid cancerous tumorsarising from any organ of the body where the tumor has its own or aproximate blood supply provided by a bodily lumen (e.g., artery) thatcan be isolated. Examples of cancers that can be treated using methodsdescribed herein can be, but are not limited to, pancreatic cancer, lungcancer, liver cancer, uterine cancer, colon cancer, or brain cancer.

For example, apparatuses and methods described herein can be used toisolate a targeted region in a patient's pancreas. Studies have shownthat a course of radiation prior to TAMP treatment has significantclinical benefit in patients with locally advanced pancreatic cancer.Combining these two modalities led to a significant increase in mediansurvival, a reduction of tumor markers, and downsizing of the tumor. Asimilar combination therapy administered by methods described herein mayhave clinical benefit in solid tumors in other organs and tissue areaswhere TAMP may be considered as a treatment option. Such tumors include,but are not limited to, pancreatic tumors, lung tumors, brain tumors,liver tumors, uterine tumors, and colon tumors.

In some embodiments, a method of treating a cancerous tumor can involve:first administering a course of radiation therapy targeting tissueincluding a solid cancerous tumor; second waiting a period of time forthe destructive effect of the radiation on the vasculature to takeeffect; and third administering a therapeutically effective dose of achemotherapeutic agent to an isolated section of a bodily lumen near thesolid tumor. The targeted solid tumor can be, for example, a pancreatictumor, a lung tumor, a brain tumor, a liver tumor, a uterine tumor, or acolon tumor. The administration of radiation on the targeted tissue areacan include, for example, delivering approximately 20 to 50 Gy ofradiation over approximately one to five weeks in approximately one to25 sessions. The period of time between administration of the radiationtherapy and administration of the chemotherapeutic agent can be selectedto maximize the devascularization of the tissue surrounding the tumor.Depending on various factors including the specific course of radiationand the specific tissue area or organ, this period of time can be, forexample, approximately one to six months, as short as two weeks, or aslong as six months. Examples of suitable chemotherapeutic agents includedoxorubicin, erlotinib hydrochloride, everolimus, 5-FU, flurouracil,folfirinox, gemcitabine hydrochloride, gemcitabine-cisplatin,gemcitabine-oxaliplatin, irinotecan hydrochloride liposome, leucovorin,mitomycin C, mitozytrex, mutamycin, oxaliplatin, paclitaxel, paclitaxelalbumin-stabilized nanoparticle formulation, or sunitinab malate or acombination of these drugs. In some embodiments, the section of thebodily lumen near the cancerous tumor can be isolated by the use of acatheter device to deliver the chemotherapeutic agent. In someembodiments, the catheter device can be used to increase theintraluminal pressure in the isolated section of the bodily lumen toachieve increased tissue penetration.

In some embodiments, a method of treating a cancerous tumor can involve:first administering a targeted dose of radiation to tissue including asolid tumor; second waiting a period of time; third isolating an areacontaining a cancerous tumor; and fourth administering a localizedtherapeutically effective dose of a chemotherapeutic agent. Similar toother methods described herein, the targeted solid tumor may be, forexample, a pancreatic tumor, a lung tumor, a brain tumor, a liver tumor,a uterine tumor, or a colon tumor. The administration of radiation onthe targeted tissue area can include, for example, deliveringapproximately 20 to 50 Gy of radiation over approximately one to fiveweeks in approximately one to 25 sessions. The period of time betweenadministration of the radiation therapy and administration of thechemotherapeutic agent can be selected to maximize the devascularizationof the tissue surrounding the tumor. Depending on various factorsincluding the specific course of radiation and the specific tissue areaor organ, this period of time can be, for example, at least a month. Theisolated area can be, for example, an artery that is in proximity to thetumor. In some embodiments, a catheter device can be used to isolate thearea. The catheter device can be used to increase the intraluminalpressure in the isolated artery. The isolated area can be, for example,the area of tissue involving the tumor. Examples of suitablechemotherapeutic agents include doxorubicin, erlotinib hydrochloride,everolimus, 5-FU, flurouracil, folfirinox, gemcitabine hydrochloride,gemcitabine-cisplatin, gemcitabine-oxaliplatin, irinotecan hydrochlorideliposome, leucovorin, mitomycin C, mitozytrex, mutamycin, oxaliplatin,paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, orsunitinab malate or a combination of these drugs.

In some embodiments, a method of treating a cancerous tumor can involve:administering a course of radiation therapy to tissue including a solidtumor; isolating the proximal and the distal part of the vasculatureclosest to the tumor to produce an isolated arterial segment; decreasingthe intraluminal pressure of the isolated arterial segment to the levelof the interstitium; and administering a therapeutically effective doseof a chemotherapeutic drug. The course of the radiation therapy candecrease tissue efflux of the chemotherapeutic drug. In someembodiments, the vasculature can be isolated using a double ballooncatheter positioned to exclude both the side and terminal branches ofthe artery. The chemotherapeutic drug can pass across the artery walland into the surrounding tissue via a pressure gradient generated by theincrease in the intraluminal pressure above the interstitial pressure.In some embodiments, the method can additionally include waiting aperiod of time following the step of administering the course ofradiation therapy. The period of time between administration of theradiation therapy and administration of the chemotherapeutic agent canbe selected to maximize the devascularization of the tissue surroundingthe tumor. For example, depending on various factors including thespecific course of administering the radiation therapy and the specifictissue region, this period of time can be at least two weeks. Thetargeted solid tumor can be, for example, a pancreatic tumor, a lungtumor, a brain tumor, a liver tumor, a uterine tumor, or a colon tumor.The chemotherapeutic drug can be, for example, a single chemotherapeuticor a combination of chemotherapeutic drugs.

FIG. 5 is a flowchart illustrating a method 500 of treating a tumorinvolving the use of radiation. In particular, the method involvesadministering a course of radiation therapy to a target area, at 502.For example, an amount of radiation (e.g., 20-50 Gy) can be administeredto a patient in multiple sessions (e.g. 1-25 sessions) over a period oftime (e.g., a few days to six months). The target area can be a tissuearea including a tumor. The method then optionally includes waiting aperiod of time for the radiation therapy to devascularize the tissue inthe target area, at 504.

The method 500 further includes introducing a catheter (e.g., thecatheter device 100) into a mammalian body into a bodily lumen (e.g.,artery), at 506. The catheter can be advanced to a target area, at 508,and used to isolate the target area, at 510. In some embodiments, thecatheter can include two occlusion members (e.g., occlusion elements102, 104) that can be deployed (e.g., inflated) to isolate a segment ofthe bodily lumen to exclude the segment from its side and terminalbranches. After the occlusion elements are deployed, an agent can beinjected through an injection port of the catheter device to theisolated segment disposed between the two occlusion members, at 512. Insome embodiments, a contrast dye can be can be injected into theisolated segment and the surrounding area can be visualized to determinewhether the segment has been correctly isolated. For example, theinjection of contrast through the infusion port can ensure that no extravessels or bodily lumens are included in the isolated area. If desired,the catheter can be moved and the procedure repeated until the cliniciancan confirm that the catheter is correctly positioned. After thepositioning of the catheter is confirmed, a therapeuticcell/biologic/agent can be introduced to the isolated segment throughthe infusion port.

In some embodiments, the step of administering the radiation therapy(502) can occur during and/or after the steps of introducing thecatheter into the mammalian body (506), advancing the catheter to thetarget area (508), isolating the target area (510), and/or injecting atherapeutic agent into the target area (512). In some embodiments, oneor more steps of the method 500 can be repeated before, during, and/orafter other steps of the method 500.

FIGS. 6A and 6B schematically illustrate the effects of radiation on thevasa vasorum microvasculature in tissue surrounding an isolated segment620 of a bodily lumen 610. By reducing the microvasculature, theradiation therapy reduces drug washout and increases drug tissueconcentration when a drug is delivered to the area using methodsdescribed herein, such as, for example, TAMP. FIG. 6A depicts an area oftissue surrounding an isolated segment 620 of a bodily lumen 610 priorto radiation therapy. FIG. 6B depicts the area of tissue after radiationtherapy. After the radiation, the number of microvasculature connections632 (e.g., micro-vessels extending from the isolated section 620 to thevenous system 630) is reduced, thereby allowing a greater concentrationof an infused drug 660 to remain in the tissue area.

As depicted in FIGS. 6A and 6B, a catheter device 600 can be used todeliver the infused drug 660 to the target area. The catheter device 600can be similar to other catheter devices described herein (e.g.,catheter device 100 and catheter device 300). For example, the catheterdevice 600 has a first occlusion element 602 and a second occlusionelement 604, which are coupled to distal end portions of a firstcatheter 601 and a second catheter 603, respectively. The catheterdevice 600 also includes a port 605 for delivering the infused drug 660to the isolated segment 620 between the first occlusion element 602 andthe second occlusion element 604. Once the infused drug 660 is deliveredto the isolated segment 620, it can pass through a wall 612 of thebodily lumen 610 into surrounding tissue.

Radiation Therapy

In methods described herein, radiation therapy can include, for example,external-beam radiation therapy delivered by X-rays, gamma rays, protonbeams, or other appropriate sources. Radiation therapy damages cells bydestroying the genetic material that controls how cells grow and divide.While both healthy and cancerous cells are damaged by radiation therapy,the goal of radiation therapy is to destroy as few normal, healthy cellsas possible. The radiation therapy described herein can be targeted asnarrowly as possible to the solid tumor(s) being treated or the tissueclosely surrounding the solid tumor(s).

Typically, a radiation treatment plan is individualized for a patient,based upon detailed imaging scans showing the location of a patient'stumor(s) and the normal areas around it. The amount of radiation thatnormal tissue in different parts of the body can safely receive is knownto one skilled in the art. Computed tomography (CT) scans are mostfrequently employed, but magnetic resonance imaging (MRI), positronemission tomography (PET), and ultrasound scans may also be used. Aradiation oncologist determines the exact area that will be treated, thetotal radiation dose that will be delivered to the tumor, how much dosewill be allowed for the normal tissues around the tumor, and the safestangles (paths) for radiation delivery. Radiation doses for cancertreatment are measured in Gy, which is a measure of the amount ofradiation energy absorbed by one kilogram of human tissue. Differentdoses of radiation are needed to kill different types of cancer cells.Patients can receive external-beam radiation therapy in daily treatmentsessions over the course of several weeks. The number of treatmentsessions depends on many factors, including the total radiation dosethat will be given. For example, one dose, which constitutes a fractionof the total planned dose of radiation, can be given each day. In adifferent instance, two treatments a day can be given.

As will be appreciated by one skilled in the art, the course ofradiation therapy appropriate for use in the method of the presentinvention will depend on the specific cancerous tumor being treated. Thespecific dose of radiation, the duration of the radiation, and thenumber of treatments for any particular individual will depend upon avariety of factors including the type of cancer, the size of thetumor(s), and the patient's age and medical history including, forexample, the amount of radiation previously received. Concurrentchemotherapy may also impact the dose of radiation given.

When treating a pancreatic cancer, for example, the course of radiationtherapy can be approximately 20 to 50 Gy of radiation delivered inapproximately one to 25 treatments over approximately one to five weeks.Alternatively, two to five sessions of radiation can be given over aperiod of approximately a week. For certain types of cancer, the amountof radiation therapy delivered may be as low as one Gy. In preferredembodiments, the course of radiation therapy can be approximately 40 to50 Gy of radiation delivered in approximately 22 to 25 treatments overapproximately four to five weeks. As may be appreciated by one skilledin the art, the amount of radiation therapy useful in methods describedherein is that necessary to devascularize the solid tumor of interestthus allowing the TAMP technique to be used advantageously.

In methods described herein, after administering the radiation therapy,a physician may wait for a period of time before administeringchemotherapy such that the tumorous tissue can die (e.g., necrosis) orbecome devascularized. In some embodiments, this period of time can beselected to maximize devascularization of the solid tumor and/or tissuecontaining the solid tumor. In some embodiments, this period of time canbe selected to maximize the effect of the chemotherapy based on asufficient amount of devascularization. In certain instances, the timeperiod that elapses before administering chemotherapy can be at least amonth. In other instances, the period of time is approximately two weeksto six months.

Chemotherapeutics

Specific chemotherapeutics can be selected based on the particular solidcancerous tumor that is to be treated. For example, the followingchemotherapeutic agents and others may be used in the treatment ofpancreatic cancer: doxorubicin, erlotinib hydrochloride, everolimus,5-FU, flurouracil, folfirinox, gemcitabine hydrochloride,gemcitabine-cisplatin, gemcitabine-oxaliplatin, irinotecan hydrochlorideliposome, leucovorin, mitomycin C, mitozytrex, mutamycin, oxaliplatin,paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, orsunitinab malate. In some embodiments, a combination of agents may beemployed. For example, when treating pancreatic cancer, a combination ofgemcitabine hydrochloride (Gemzar®) and paclitaxel albumin-stabilizednanoparticle formulation (Abraxane®) may be used.

The above-described chemotherapeutic agents are available from a varietyof corporate sources licensed to provide such agents for human use.Generic formulations of non-proprietary chemotherapeutics are typicallyavailable from a variety of manufacturers. A list of these licensedsuppliers is available from the U.S. Food and Drug Administration's“Approved Drug Products with Therapeutic Evaluations,” commonly known asthe “Orange Book” (http://www.accessdata.fda.gov/scripts/cder/ob/).Proprietary chemotherapeutics are typically available from onemanufacturer, also identifiable in the Orange Book. For example, thecorporate source for Gemzar® is Eli Lilly and Company (Indianapolis,Ind.) and Celgene Corporation (Summit, N.J.) supplies Abraxane®.

Methods described herein can use an amount of chemotherapeutic agentthat is known to be therapeutically effective at treating a tumor. Forexample, the amount of chemotherapeutic agent that is used can be basedon the Prescribing Information for a particular chemotherapeutic drug. Aphysician can adjust the amount of the chemotherapeutic agent to anamount that is appropriate for use with the TAMP techniques describedherein.

In methods described herein, a therapeutic agent (e.g., chemotherapydrug) can be delivered via rapid infusion (e.g., injected directly intoan artery over a period of minutes, intravenous infusion (e.g., througha drip or pump over a period of approximately 20 minutes to a fewhours), or continuous infusion (e.g., through a continuation infusionpump over a period of weeks to months). The infusion of the drug into anisolated space increases the intraluminal or interior pressure of thevessel to above the interstitial pressure of the surrounding tissue andthe pressure gradient forces the drug across a vessel wall and into thesurrounding tissue.

Catheter Device

In some embodiments, methods described herein can use a catheter devicesuch as, for example, a double occlusion balloon to isolate a segment ofa bodily lumen (e.g., artery) and allow infusion of a therapeutic agent(e.g., chemotherapy drug) into the isolated segment between the balloonafter they are inflated. For example, methods disclosed herein may usecatheter devices such as those described in U.S. patent application Ser.No. 14/293,603, filed Jun. 2, 2014, titled “Devices, methods and kitsfor delivery of therapeutic materials to a target artery,” now issued asU.S. Pat. No. 9,457,171, and U.S. patent application Ser. No.14/958,428, filed Dec. 3, 2015, titled “Occlusion catheter system andmethods of use,” which are incorporated herein by reference. Briefly, acatheter device suitable for isolating a section of a bodily lumen neara solid tumor includes, but is not limited to, features and functionssuch as, for example: (1) selective isolation of the targeted portion ofthe portion of the artery for targeted delivery of the therapeutic agentto the solid tumor; (2) an infusion port allowing first, injection ofcontrast into the isolated segment to allow direct visualization of theorigin of the branches of the artery supplying the cancerous tissue, andsecond, introduction of chemotherapeutic drugs; and (3) a self-containedassembly unit with easy retrieval after completion of the procedure. Inone embodiment, the catheter device includes expandable occlusionelements in the form of inflatable balloons that can be used to isolatea proximal and distal end of a bodily lumen of interest.

Methods described herein can include, for example, introducing acatheter device into a splenic artery of the pancreas. The catheterdevice can have, for example, two lumens—one for inflation/deployment ofthe balloons/occluding elements and a second for introduction of theinfusate (e.g., therapeutic agent) to the space between the twoballoons. The catheter can be advanced to a target portion of thesplenic artery. A region of the target portion of the splenic artery isselectively isolated and the infusate is injected into the isolatedregion. In some embodiments, the method can include advancing at least aportion of the catheter device to an ostium of a celiac artery, itshepatic branch (and its branches), or if necessary, the superiormesenteric artery, depending on a patient's anatomy. In someembodiments, a contrast dye is injected into the isolated region toconfirm exclusion of side branches before injecting the infusate.

In some embodiments, the catheter device can have one or more featuresto achieve a desired effect on a specific anatomy of tumors. Forexample, there may be: (1) a separate inflation lumen for the proximaland the distal occluders/balloons to allow different sizeoccluders/balloons proximally and distally; (2) slidable catheters toallow the distance between the occluders/balloons to be adjusted; and(3) a sensor at the tip to monitor pressure in the isolated segment ofthe bodily lumen.

FIGS. 4A and 4B schematically depict an example of a catheter device 300disposed within a bodily lumen 310 (e.g., artery) and the dispersal ofan infused substance 360 through the bodily lumen 310 into surroundingtissue. The catheter device 300 can be similar to other catheter devices(e.g., catheter device 100) described herein. For example, catheterdevice 300 includes a first occlusion element 302 and a second occlusionelement 304 for occluding a portion 320 of bodily lumen 310. The firstocclusion element 302 is coupled to a distal end portion of a firstcatheter 301, and the second occlusion element 304 is coupled to adistal end portion of a second catheter 303. The occlusion elements 302,304 are filter elements that can be moved between a collapsedconfiguration for insertion of the catheter device 300 into a body of apatient (e.g., into an artery) and an expanded or dilated configuration,as shown in FIGS. 4A and 4B, for occluding a portion of a bodily lumen.The occlusion elements 302, 304 when in the collapsed configuration havea smaller outer perimeter (or diameter) than when in the expandedconfiguration.

As depicted in FIGS. 4A and 4B, the catheter device 300 can be used toisolate a segment 320 of a bodily lumen 310 within the space definedbetween the first occlusion element 302 and the second occlusion element304. The catheter device 300 can include a lumen in fluid communicationwith port or opening 305 for delivering an agent 360 (e.g., a dye or achemotherapy drug) to the space between the first occlusion element 302and the second occlusion element 304. The first catheter 301 can definethe lumen and the opening 305. The opening 305 can be disposed on thedistal end portion of the first catheter 301 distal to the firstocclusion element 302. The second catheter 303 can be movably disposedwithin a lumen defined by the first catheter 301 such that the secondcatheter 303 can be moved relative to the first catheter 301 to move thesecond occlusion element 304 relative to the first occlusion element302. According to some embodiments of the disclosure, the secondocclusion element 304 can be moved toward the first occlusion element302 to increase pressure within the isolated segment 320. The increasedpressure can be used, for example, to drive delivery of the agent 360through the wall 312 of the bodily lumen 310 and into the surroundingtissue.

In some embodiments, the catheter device 310 can have a sensor such as apressure transducer 306 that may assist with achieving an optimalpressure within an occluded arterial segment for optimizingtrans-arterial diffusion of an infused substance during a method ofcancer treatment (e.g., a TAMP procedure). The pressure transducer 306may be disposed along the catheter device 300 in the isolated arterialsegment 320 (e.g., disposed between the first occlusion element 302 andthe second occlusion element 304 (as depicted in FIGS. 4A and 4B)). Thepressure transducer 306 can be disposed on one of the catheters 301,303, or disposed on one of the occlusion elements 302, 304. The pressuretransducer 306 can be designed to measure an intraluminal pressure ofthe isolated segment 320. The pressure measurements may be used toadjust the intraluminal pressure of the isolated segment 320 to apredetermined or optimal pressure level. A physician may use thepressure measurements to determine a rate of infusing a drug or othertherapeutic material into the isolated segment 320 in order to decreaseor increase the intraluminal pressure of the isolated segment 320. Forexample, a physician can increase the rate of infusion of a drug toincrease the intraluminal pressure of the isolated segment 320 above thepressure of tissue surrounding the isolated segment 320 (e.g., above thepressure of the interstitium) to create a pressure gradient between theintraluminal space and the surrounding tissue to increase permeation ofthe infused drug through the arterial wall and into the tissue.Additionally or alternatively, a physician can increase or decrease theintraluminal pressure of the isolated segment 320 by adjusting theposition of the two occlusion elements 302, 304 relative to one another(e.g., moving the two occlusion elements 302, 304 closer or furtherapart from one another).

Determination of Therapeutic Effectiveness

The efficacy of the methods of the present invention in the treatment ofsolid cancerous tumors can be evaluated in human clinical trialsconducted under appropriate standards and ethical guidelines as setforth by the U.S. Food and Drug Administration (FDA). Such studies areconducted according to U.S. and International Standards of Good ClinicalPractice. Typically, such trials are comparison trials, in that themethod of the present invention is utilized in one cohort of patients,while one or more other cohorts receive alternative methods of treatingthe tumors. The alternative methods can include, for example, treatmentwith systemic chemotherapy alone.

A clinical trial for the treatment of cancerous tumors may have aprimary objective of evaluating survival in patients who undergoradiation therapy followed by intra-arterial delivery of achemotherapeutic agent to an isolated arterial section near the solidtumor after a suitable interval of time elapses. The second objective ofsuch a trial is to assess tumor response by known imaging techniques atthe primary site of application of the chemotherapeutic agent. Inparticular, the size of the tumor before and after treatment can bedetermined and evaluated across different treatment methods. Inaddition, the conversion rate from unresectable or borderline resectableto potentially resectable or resectable tumors can be determined. Theresults may be analyzed using standard statistical techniques known tothose skilled in the art.

The following examples, including clinical studies, are offered by wayof illustration and not by way of limitation.

Examples: Experiments with Pig Tissue

FIG. 7 is an image 700 of a pancreatic tumor 710 of a pig aftertreatment with the TAMP method. The method involved occluding the celiacartery of the pig with a double balloon catheter, rapidly infusing dyeat six milliliters per minute for ten minutes into the isolated segmentof the celiac artery, and harvesting the tissue next to the celiacartery. As depicted, the infused dye has permeated into the harvestedtissue.

FIG. 8 is an image 800 of tissue surrounding the celiac artery of a pigafter treatment with the TAMP method. The method involved occluding theceliac artery of the pig with a double balloon catheter (i.e., a ballooncatheter with occlusion elements or balloons 802) and rapidly infusingdye at six milliliters per minute for ten minutes into the isolatedsegment of the celiac artery. The image shows the tissue surrounding theceliac artery in situ within ten sections after initiating the rapidinfusion of the dye. As depicted in FIG. 8, the dye 804 has penetratedinto the surrounding tissue via the vasa vasorum microvasculature.

FIGS. 11 and 12 relate to an experiment conducted on a pig to evaluatethe effect of radiation on tissue penetration of drugs/molecules usingthe TAMP technique. The experiment involved administering radiationtreatment to a left groin area in a pig and comparing the penetration ofa dye introduced using the TAMP technique in the left groin area(referred to herein as the test 1200) versus the penetration of the dyein the right groin area (referred to herein as the control 1210). AYucatan pig was anesthetized for a CT scan of the femoral artery to planthe radiation treatment. Both femoral arteries were accessed for theplacement of sterile gold fiducial markers to mark the areas of interestfor comparison following the radiation treatment and infusion of dye.The left groin area was treated with a single radiation session usingthe CyberKnife® system at 15 Gy outside the artery adjacent to the goldmarker. FIG. 11 depicts an image 1100 of the left groin area with thegold marker 1106. One month following radiation treatment, with theanimal under general anesthesia, a percutaneous exposure of the left andright femoral artery was completed. From the left carotid artery, adouble balloon catheter 1110 was advanced to the area of the leftfemoral artery and a proximal balloon 1102 and a distal balloon 1104 ofthe catheter 1110 were positioned and inflated adjacent to the goldfiducial marker 1106, as shown in FIG. 11. The catheter 1110 isolatedthe relevant segment of the left femoral artery adjacent to the goldfiducial marker 1106 to ensure exclusion of any large side branches andto achieve optimal intravascular pressure in the isolated segment. Asyringe pump was then used to inject a dye at six milliliters per minutefor approximately 30 seconds through an infusion port between the twoballoon catheters. The same procedure was repeated for the right femoralartery. At the conclusion of the procedures in the left and rightfemoral arteries, the area of dye penetration around the blood vesselswere measured. As shown in FIG. 12, there was approximately a three-foldincrease in penetration on the irradiated left side (i.e., test 1200) ascompared to the control right side (i.e., control 1210).

Examples: Clinical Studies of Treating Pancreatic Cancer

A post-market registry study was conducted to assess patient survivaland clinical outcomes using the RenovoCath™ RC120 catheter (RenovoRx,Los Altos, Calif.) in a clinical, prospective observational setting whenused to deliver a chemotherapeutic to the pancreas as described in Table1.

TABLE 1 Study Title: Inter-Arterial Treatment of Pancreatic Cancer Usingthe RenovoCath ™ RC120 Catheter Development Post market Phase: StudyType: Global Multicenter, Prospective, Observational Registry ProductThe RenovoCath ™ RC120 Catheter is an Description: endovascularmulti-lumen, two handled catheter designed to isolate variable segmentsof arteries supplying the target organ using two slideable, compliantballoons. Study Patients with pancreatic cancer, with and without priorPopulation: radiation therapy Chemotherapeutic Gemcitabine injection(Gemzar ®) agent: Primary 1. Evaluate survival in patients diagnosedwith Objectives pancreatic cancer who undergo intra-arterial delivery ofchemotherapeutic agents to the pancreas 2. Assess tumor response in theprimary site of application as assessed by imaging Primary 1. SurvivalEndpoints 2. Tumor response 3. Performance of RenovoCath in definedpopulation (pancreatic cancer) in a clinical setting Secondary 1. Assessconversion rate from unresectable or Objective/ borderline resectable topotentially resectable or Endpoints resectable pancreatic cancer 2.Further define and analyze potential selection criteria for patients whopresent with locally advanced pancreatic cancer that may benefit fromthe intra- arterial procedure Study Sites: Multicenter

After patient screening and enrollment, eligible patients underwentselective catheterization introduced via the femoral artery into theceliac axis into the splenic, hepatic and/or superior mesentericartery(ies) using the TAMP technique as described above for thelocalized delivery of gemcitabine followed by embolization agentlipiodol. An interventional radiologist used the RenovoCath™ RC 120catheter to optimize drug delivery to the tumor(s). At the conclusion ofthe case, the femoral artery arteriotomy was sealed and patientmonitored as per standard institutional protocol.

All patients enrolled during the two-year registry enrollment periodwere followed periodically for survival outcome. Patients were contactedby telephone at the following intervals after the final intra-arterialtreatment: 6 months±30 days, 1 year±30 days and 2 years±30 days.Patients were assessed for serious adverse events with specificattention to events related to local delivery of chemotherapeutic agentsto the pancreas and device performance.

FIG. 9 shows the superiority of the TAMP technique as compared tostandard systemic chemotherapy. Graph 900 shows the increase in survivalbenefits in patients treated with TAMP compared to those treated with asystemic intravenous infusion of the same drug (i.e., gemcitabine). Line902 represents the survival percentage of patients completing eighttreatments of gemcitabine using the TAMP technique. Line 904 representsthe survival percentage of patients completing more than two treatmentsof gemcitabine using the TAMP technique. And line 906 represents thesurvival percentage of patients given systemic infusion of gemcitabine,the results of which are taken from Chauffert et al., Ann. Oncol., 2008,19:1592-9. As depicted in FIG. 9, the survival rates of the patientstreated with the TAMP technique (i.e., lines 902, 904) were greater thanthe survival rates of the patients given systemic infusion of the samedrug (i.e., line 906).

FIG. 10 is a graph 1000 illustrating the effect of the TAMP technique onpatient survival after radiation therapy compared with the effect of theTAMP technique with no radiation therapy. Fifteen patients with locallyadvanced pancreatic cancer were treated with gemcitabine in adose-escalated protocol administered in four cycles using the TAMPtechnique. Each cycle consisted of two treatments two weeks apart. Theefficacy data for the fifteen patients who received more than one cycleof TAMP treatment are shown in FIG. 6. Of these fifteen patients, fivehad no prior treatment of any kind, five had prior systemicchemotherapy, and five received radiation in additional to systemicchemotherapy prior to entering the study. On average, patients receivedradiation one to six months prior to enrolling in the study andreceiving TAMP therapy. For the three groups of patients, the mostpronounced survival benefit was seen in patients who had receivedradiation prior to the initiation of TAMP therapy. Specifically,patients with prior radiation had a significant improvement in survivalcompared to the ones that had either no prior treatment or only priorsystemic chemotherapy with no radiation therapy. Patients were treatedwith TAMP therapy, regardless of their prior history. The dotted portionof the bars (1020, 1030) indicates the average time from diagnosis tothe first TAMP therapy, while the clear portion of the bars (1010, 1022,1032) indicates the average time from the first TAMP therapy to death.

This study demonstrated that a course of radiation prior to chemotherapytreatment administered via the TAMP technique has significant clinicalbenefit in patients with locally advanced pancreatic cancer. Combiningthese two modalities led to significant increase in median survival,reduction of tumor markers, and downsizing of the tumor. It is expectedthat a similar combination therapy would have clinical benefit in anysolid tumors where diffusion-dependent infusion of a chemotherapeuticmay be considered as a treatment option.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Where schematics and/or embodiments described above indicatecertain components arranged in certain orientations or positions, thearrangement of components may be modified. While the embodiments havebeen particularly shown and described, it will be understood thatvarious changes in form and details may be made. Although variousembodiments have been described as having particular features and/orcombinations of components, other embodiments are possible having acombination of any features and/or components from any of embodiments asdiscussed above. For example, the size and specific shape of the variouscomponents can be different from the embodiments shown, while stillproviding the functions as described herein. Furthermore, each featuredisclosed herein may be replaced by alternative features serving thesame, equivalent or similar purpose, unless expressly stated otherwise.Thus, unless expressly stated otherwise, each feature disclosed is oneexample only of a generic series of equivalent or similar features.

Where methods and/or events described above indicate certain eventsand/or procedures occurring in certain order, the ordering of certainevents and/or procedures may be modified. Additionally, certain eventsand/or procedures may be performed concurrently in a parallel processwhen possible, as well as performed sequentially as described above.

What is claimed is:
 1. A method, comprising: devascularizing a targetarea including a tumor to reduce the microvasculature in the target areaby administering a dose of radiation to the target area; inserting acatheter device into a vessel, the catheter device including a firstoccluder and a second occluder; isolating a segment of the vesselproximate to the target area using the first occluder and the secondoccluder; delivering a dose of an agent to the devascularized targetarea from the isolated segment via the catheter device.
 2. The method ofclaim 1, wherein the agent is a chemotherapeutic agent.
 3. The method ofclaim 2, wherein the chemotherapeutic agent includes one or morecompounds selected from a group consisting of: doxorubicin, erlotinibhydrochloride, everolimus, 5-FU, flurouracil, folfirinox, gemcitabinehydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin,irinotecan hydrochloride liposome, leucovorin, mitomycin C, mitozytrex,mutamycin, oxaliplatin, paclitaxel, paclitaxel albumin-stabilizednanoparticle formulation, and sunitinab malate.
 4. The method of claim2, wherein the chemotherapeutic agent includes at least two compoundsselected from a group consisting of: doxorubicin, erlotinibhydrochloride, everolimus, 5-FU, flurouracil, folfirinox, gemcitabinehydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin,irinotecan hydrochloride liposome, leucovorin, mitomycin C, mitozytrex,mutamycin, oxaliplatin, paclitaxel, paclitaxel albumin-stabilizednanoparticle formulation, and sunitinab malate.
 5. The method of claim1, wherein the catheter device defines a lumen and an infusion port, thelumen in communication with the infusion port and configured to deliverthe dose of the agent to the segment.
 6. The method of claim 5, whereinthe infusion port is disposed on the catheter device between the firstoccluder and the second occluder such that the infusion port can deliverthe dose of the agent to the segment isolated between the first occluderand the second occluder.
 7. The method of claim 1, wherein the tumor isa pancreatic tumor.
 8. The method of claim 1, wherein the insertion ofthe catheter device into the vessel occurs after the administering ofthe dose of radiation.
 9. The method of claim 1, wherein the delivery ofthe dose of the agent occurs after a predefined period of time followingthe administering of the dose of radiation.
 10. The method of claim 9,wherein the predefined period of time is between two weeks and sixmonths.
 11. The method of claim 1, further comprising administering oneor more additional doses of radiation to the target area, wherein thedose of radiation and the additional doses of radiation are administeredduring a period of one to five weeks, and wherein the dose of radiationand the additional doses of radiation include an amount of radiationtotaling between 20 and 50 gray (Gy).
 12. The method of claim 11,wherein the amount of radiation is selected based on one or morecharacteristics of the tumor, the one or more characteristics includingat least one of: a location of the tumor, and a size of the tumor. 13.The method of claim 1, wherein the dose of the agent is a first dose ofa first agent, and further comprising delivering a second dose of asecond agent to the isolated area of the artery.
 14. The method of claim13, wherein the first agent is a dye and the second agent is achemotherapeutic agent.
 15. The method of claim 13, wherein the firstagent is a first chemotherapeutic agent and the second agent is a secondchemotherapeutic agent different from the first chemotherapeutic agent.16. A method, comprising: devascularizing a target area including atumor to reduce the microvasculature in the target area by administeringa dose of radiation to the target area; isolating a segment of a vesselproximate to the target area; decreasing an intraluminal pressure of thesegment to a level of pressure of an interstitial space between thevessel and the target area; and delivering a dose of an agent to thedevascularized target area from the isolated segment via a catheterdevice while increasing the intraluminal pressure to greater than thepressure of the interstitial space between the vessel and the targetarea.
 17. The method of claim 16, wherein the segment of the vessel isisolated using a catheter device including a first occluder and a secondoccluder.
 18. The method of claim 17, wherein the catheter devicefurther includes a pressure sensor configured to measure theintraluminal pressure of the segment.
 19. A method, comprising:devascularizing a target area to reduce the microvasculature in thetarget area, the target area including a tumor; inserting a catheterdevice into a vessel, the catheter device including a first occluder anda second occluder; isolating a segment of the vessel proximate to thetarget area using the first occluder and the second occluder; deliveringa dose of an agent to the devascularized target area from the isolatedsegment via the catheter device.